This application examines the underlying signaling mechanisms that are involved in impulsivity as it changes across development (juvenile, adolescent, and adult), sex, pathology, and drug exposure. The overarching goal of this application is to: To identify dysfunctional neuronal circuit(s) and signaling mechanisms associated with impulsive behaviors and identify novel prevention approaches for intervention. We propose a multi-faceted approach that encompasses behavioral and molecular analyses to examine neuronal function within well-defined neural pathways in the rodent brain of both males and females. We have two Co-PIs, who will be running different aspects of these projects indepdently and interdependently at various times within the 5 year period. We build on our new data that show that elevated D1 dopamine receptors in the prelimbic prefrontal cortex of the rat increase impulsivity and other risky behaviors. Aim 1 will identify and confirm neuronal pathways underlying impulsivity using both a reward-associated impulsivity task of impulsive choice (e.g., delayed discounting) and a motor-related task of impulsive action (e.g., the stop signal reaction time task). We will analyze receptors on projections from the prelimbic prefrontal cortex, the basolateral amygdala, and the orbital frontal cortex as they innervate the nucleus accumbens and the basolateral amygdala. Differential expression levels of D1 and alpha2A noradrenergic receptors are hypothesized to mediate these behaviors. We will use laser microdissection (LMD) and quantitative, real-time PCR for this initial assessment, followed by mechanistic confirmation with experimental use of viral vectors that selectively over-express these receptors in glutamate neurons in a given region. In Aim 2, we will determine effective doses (ED50s) of methylphenidate, atomoxetine, and guanficine on impulsivity at different ages and across sex. Due to their different selectivity for dopamine and alpha2A receptors, we expect that different signaling pathways will be uniquely activated at different ages. The derived ED50s will then be used in a juvenile exposure paradigm that is predicted to effectively prevent impulsive behaviors in adulthood. In Aim 3, samples from Aim 1 (viral over-expression) and Aim 2 (preventative interventions) will be analyzed with a bioinformatics approach with microarray and microRNAs analyses to identify convergent signaling pathways involved in impulsive behaviors and its effective intervention. Together, these studies will provide information on the developmental profile of the mechanisms underlying impulsivity as it is influenced by sex and medication. PUBLIC HEALTH RELEVANCE: We will use laser microdissection of glutamate neurons in specific projection pathways into the nucleus accumbens to identify the underlying signaling mechanisms that are associated with impulsive choice and action. Drug treatments determined to be effective in reducing impulsive behaviors will be coupled with genetic engineering to identify novel cell signaling pathways with microarrays and microMRNA analyses. The goal of the proposed work is to elucidate a preventative therapeutic approach to impulsive behaviors.